Ischemia, the clinical term for oxygen starvation, is the leading cause of death in the world. The most common forms of ischemia leading to death are caused by interruptions of blood flow. Heart disease, stroke, and severe blood loss from traumatic injuries are examples of ischemia that are responsible for over 50% of all deaths.
In clinical situations of ischemia, the immediate goal is to restore blood flow to the patient as quickly as possible. If blood flow is restored within a suitable time period, tissue damage can be averted. However, a significant delay in restoring blood flow leads to a second condition known as ischemia-reperfusion injury. Reperfusion injury begins when harmful reactive oxygen species are formed following the ischemic episode. Reactive oxygen species originate by complex, spontaneous free radical reactions that damage lipids, proteins and DNA and can eventually kill cells. Lipids in cellular membranes are the primary early targets of attack by oxygen in the blood resulting in formation of lipid peroxides which are extremely cytotoxic (Kilgore K S and Lucchesi B R. 1993, Clin Biochem 26:359–70; Kloner R A., 1993, J Am Coll Cardiol 21:537–45; Huynh T T, et al., 1999, J Surg Res 84:223–32; Kesavulu M M, et al., 2001, Diabetes Res Clin Pract 53:33–9).
Ischemia-reperfusion injury can develop gradually after an ischemic event and may cause irreversible damage to tissues. Clinical examples include cardiac contractile dysfunction, arrhythmias and irreversible myocyte damage (heart cell death) following myocardial infarction (heart attack). Although no drugs are currently available for treating ischemia-reperfusion injury, the damage caused by ischemia-reperfusion injury is preventable and reversible if certain treatments are administered in a timely fashion. The most clinically relevant treatments involve administration of antioxidants. Endogenous antioxidants such as glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase act as a primary defense mechanism. Additionally, dietary vitamin E can play a secondary role in attenuating ischemia-reperfusion injury. Administration of exogenous antioxidant supplements before or after reperfusion has shown some utility in experimental systems (Abunasra H J et al., 2001, Eur J Cardiothorac Surg. 20: 153–8; Cuzzocrea S, et al., 2001, Pharmacol Rev Mar 53:135–59; Dhalla N S, et al., 2000, Cardiovasc Res 47:446–56; Galang N, et al, 2000, Toxicology 148:111–8; Hangaishi M, et al., 2001, Biochem Biophys Res Commun 285:1220–5; Kanamasa K, et al., 2001, Acta Cardiol 56: 181–6; Laurindo F R, et al., 1991, Circulation 83:1705–15; Li Q, 2001, Circulation 103: 1893–8; Prasad K, et al., 1996, Can J Cardiol 12:1083–91; Rowland R T, et al.,1995, Surgery 118:446–52; Van Remmen H, et al., 2001, Am J Physiol Heart Circ Physiol 281 :H1422–32). However, SOD treatment has failed to show a beneficial effect in human clinical trials (Flaherty J T, 1994, Circulation 89: 1982–91).
Allene Oxide synthase serves as an antioxidant by rapidly eliminating lipid hydroperoxides from the system (U.S. Pat. No. 6,132,711; Pan Z, et al., 1998, J Biol Chem 273: 18139–18145). The present invention provides a novel method for reducing ischemia-reperfusion injury based on the administration of allene oxide synthase.